Particulate air pollutants (particulate matter;PM) are ubiquitous in the environment. Increases in human respiratory and cardiovascular dysfunction, disease, and mortality have been linked to both short- and long- term exposures to PM. Currently, specific mechanisms of action at the molecular and cellular levels and targeted therapies to reduce the detrimental effects of PM exposures in humans remain undefined. This is, in part, because the gene products that translate the presence of PM into deleterious molecular, cellular and systemic events are essentially unknown. Preliminary data show that TRPV1 and a TRPM8 variant are activated by PM. Furthermore, activation is coupled to increased expression of cytokine/chemokine genes by lung cells in vitro and in the lung. The proposed research will investigate TRPV1, TRPM8, and other TRP family calcium channels as sensors for PM and mediators of toxicity in the lung. The molecular and physico-chemical determinants of TRP channel activation by different PM sub-types will be established using site-directed mutagenesis of TRP channels and physical and chemical modification of PM. TRPV1, TRPM8, and other PM-sensing TRP channels will also be evaluated as mediators of PM toxicity in mice. PM-Induced lung toxicity will be studies using both TRP channel antagonists and TRP channel knockout mice. Furthermore, quantifiable biomarkers that discriminate TRP channel activation in the lung by different PM will be identified and validated. These data will drive future studies of humans who experience respiratory distress during high pollution episodes. The proposed research will establish fundamental mechanisms of PM-induced pulmonary toxicity and provide key insights into mechanisms of PM-induced respiratory distress. Future studies will attempt to link the activation of specific TRP channels with environmentally-induced human respiratory distress. It is anticipated that the combined results of this research will transform future biomedical research investigating the origins of and strategies to treat respiratory disorders and diseases associated with exposure to environmental PM. PUBLIC HEALTH RELEVANCE: This research will identify and characterize proteins in the lung that may potentially determine whether a person develops health problems when they inhale polluted air. Identification of the proteins responsible for sensing and responding to inhaled air pollution as well as the mechanisms by which responses occur will ultimately allow scientists and physicians to establish effective ways to treat and/or prevent sickness due to breathing polluted air.